The United States of America, As Represented by the Secretary, Department of Health and Human Services

University System of Maryland

University of Texas System

West Virginia University

Andrew Coop

Kenner C Rice

Alexander D MacKerell, Jr

Rae Matsumoto

Charles France

Maharaj K Ticku

An opioid narcotics used for the treatment of moderate-to-severe pain that primarily exert their analgesic effects through &#x3bc; receptors. Although, traditional &#x3bc; agonists can cause undesired side effects, including tolerance, addition of &#x3b4; antagonists can attenuate said side effects. The present invention includes 4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (UMB 425) a 5,14-bridged morphinan-based orvinol precursor, along with analogs of morphine, dihydromorphine, hydromorphone, codeine, dihydrocodeine, hydrocodone and ethylmorphine. Although UMB 425 lacks &#x3b4;-specific motifs, conformationally sampled pharmacophore models for &#x3bc; and &#x3b4; receptors predict it to have efficacy similar to morphine at &#x3bc; receptors and similar to naltrexone at &#x3b4; receptors, due to the compound sampling conformations in which the hydroxyl moiety interacts with the receptors similar to orvinols. UMB 425 exhibits a mixed &#x3bc; agonist/&#x3b4; antagonist profile as determined in receptor binding. UMB 425 has mixed &#x3bc; agonist/&#x3b4; antagonist properties in vitro that translate to reduced tolerance liabilities in vivo.

Mixed &#x3bc; agonist/ &#x3b4; antagonist opioid analgesics with reduced tolerance liabilities and uses thereof

The present invention generally relates to pharmaceutical compositions comprising ethers of 3-hydroxyphenylacetic acid. The present invention also relates to therapeutic uses of the ethers of 3-hydroxyphenylacetic acid. The ethers of 3-hydroxyphenylacetic acid have the chemical structural of formula (I): where R is an aromatic or arylalkyl substituent.

Ethers of 3-hydroxyphenylacetic acid as selective gamma-hydroxybutyric acid receptor ligands

The present invention provides a method for N-deprotecting an opioid compound, a method for N-deprotecting and O-demethylating an opioid compound, a method for O-demethylating an opioid compound, and a method for O-demethylating a nonpeptidic delta agonist compound or an opioid compound having a tertiary amide with no significant reaction at amide groups.

Methods of O-demethylation and N-deprotection

Methods of o-demethylation and n-deprotection

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Baltimore, MD, United States of America

Andrew Coop